Search

Zika virus (ZIKV) is a re-emerging RNA virus that is known to cause ocular and neurological abnormalities in infants. ZIKV exploits autophagic processes in infected cells to enhance its replication and spread. Thus, autophagy inhibitors have emerged as a potent therapeutic target to combat RNA viruses, with Hydroxychloroquine (HCQ) being one of the most promising candidates. In this study, we synthesized several novel small-molecule quinoline derivatives, assessed their antiviral activity, and determined the underlying molecular mechanisms. Among the nine synthesized analogs, two lead candidates, labeled GL-287 and GL-382, significantly attenuated ZIKV replication in human ocular cells, primarily by inhibiting autophagy. These two compounds surpassed the antiviral efficacy of HCQ and other existing autophagy inhibitors, such as ROC-325, DC661, and GNS561. Moreover, unlike HCQ, these novel analogs did not exhibit cytotoxicity in the ocular cells. Treatment with compounds GL-287 and GL-382 in ZIKV-infected cells increased the abundance of LC3 puncta, indicating the disruption of the autophagic process. Furthermore, compounds GL-287 and GL-382 effectively inhibited the ZIKV-induced innate inflammatory response in ocular cells. Collectively, our study demonstrates the safe and potent antiviral activity of novel autophagy inhibitors against ZIKV.

Nowadays, nanotechnology is extensively employed in the medical profession. In this study, we used the aqueous extract of the bark of Mitragyna parvifolia to synthesize silver nanoparticles (AgNPs) by microwave-assisted green synthesis. The synthesis of AgNPs was confirmed by visual color change to brown color and characteristic surface plasmon resonance peak at 432 nm. The hydrodynamic diameter of the AgNPs was 171.81 nm having a zeta potential of −24.14 mV; Fourier Transmission Infrared Spectroscopy confirmed the presence of different functional groups on the NP surface; Scanning Electron Microscope and High-Resolution Transmission Electron Microscopy indicated predominantly circular shape of nanoparticle; Selected Area Electron Diffraction and X-ray Diffraction analyses determined the crystalline structure of AgNPs. Energy-Dispersive X-ray indicated the elemental composition and formation of AgNPs. The AgNPs were screened at different concentrations for antioxidant activity, antimicrobial, and anticancer potential in breast cancer cells (MCF-7 and MDA-MB-231). The AgNPs exhibited remarkable antioxidant, antimicrobial, and anticancer activities. The sedative and antinociceptive activities were also tested on Swiss albino mice, which showed mild sedative and very potent antinociceptive activity. However, detailed mechanistic studies are warranted in the future for clinical application of the AgNPs as a biologically active agent as well as a carrier for drug delivery.

The world urgently needs new sources of clean energy due to a growing global population, rising energy use, and the effects of climate change. Nuclear energy is one of the most promising solutions for meeting the world’s energy needs now and in the future. One type of nuclear energy, Low Energy Nuclear Reactions (LENR), has gained interest as a potential clean energy source. Recent AI advancements create new ways to help research LENR and to comprehensively analyze the relationships between experimental parameters, materials, and outcomes across diverse LENR research endeavors worldwide. This study explores and investigates the effectiveness of modern AI capabilities leveraging embedding models and topic modeling techniques, including Latent Dirichlet Allocation (LDA), BERTopic, and Top2Vec, in elucidating the underlying structure and prevalent themes within a large LENR research corpus. These methodologies offer unique perspectives on understanding relationships and trends within the LENR research landscape, thereby facilitating advancements in this crucial energy research area. Furthermore, the study presents LENRsim, an experimental machine learning tool to identify similar LENR studies, along with a user-friendly web interface for widespread adoption and utilization. The findings contribute to the understanding and progression of LENR research through data-driven analysis and tool development, enabling more informed decision-making and strategic planning for future research in this field. The insights derived from this study, along with the experimental tools we developed and deployed, hold the potential to significantly aid researchers in advancing their studies of LENR.

Summary: Zika virus (ZIKV) infection during pregnancy causes severe neurological and ocular abnormalities in infants, yet no vaccine or antivirals are available. Our transcriptomic analysis of ZIKV-infected retinal pigment epithelial (RPE) cells revealed alterations in the cholesterol pathway. Thus, we investigated the functional roles of ATP binding cassette transporter G1 (ABCG1) and sterol response element binding protein 2 (SREPB-2), two key players in cholesterol metabolism, during ocular ZIKV infection. Our in vitro data showed that increased ABCG1 activity via liver X receptors (LXRs), reduced ZIKV replication, while ABCG1 knockdown increased replication with elevated intracellular cholesterol. Conversely, inhibiting SREBP-2 or its knockdown reduced ZIKV replication by lowering cholesterol levels. In vivo, LXR agonist or SREBP-2 inhibitor treatment mitigated ZIKV-induced chorioretinal lesions in mice, concomitant with decreased expression of inflammatory mediators and increased activation of antiviral response genes. In summary, our study identifies ABCG1’s antiviral role and SREBP-2’s proviral effects in ocular ZIKV infection, offering cholesterol metabolism as a potential target to develop antiviral therapies.

Abstract Background Prescription medications such as selective serotonin reuptake inhibitors (SSRIs), commonly used to treat depression, are associated with weight gain. The role of pharmacogenomics in predicting SSRI-induced weight gain is unclear. Methods In this retrospective cohort study from participants in the Mayo Clinic RIGHT study who were prescribed citalopram, paroxetine, sertraline, or fluoxetine, our aim was to evaluate the association of metabolizer phenotype and total body weight after 6 months of SSRIs initiation. We evaluated the metabolizer phenotypes (poor/intermediate, normal, and rapid/ultra-rapid) of the cytochromes P450 enzymes genes: CYP2C9, CYP2C19, and CYP2D6 known to influence the metabolism of SSRI medications: CYP2C19 for citalopram, CYP2D6 for paroxetine, CYP2D6 and CYP2C19 for sertraline, and CYP2D6 and CYP2C9 fluoxetine. In addition, we assessed the association of metabolizer phenotype and total body weight change at six months following SSRI prescription using parametric analysis of covariance adjusted for baseline body weight and multivariate regression models. Results CYP2C19 poor/intermediate metabolizers prescribed citalopram gained significantly more weight than normal or rapid/ultra-rapid metabolizers at 6 months (TBWG %: 2.6 [95% CI 1.3—4.1] vs. 0.4 [95% CI -0.5 – 1.3] vs. -0.1 [-95% CI -1.5—1.1]; p = 0.001). No significant differences in weight outcomes at six months of treatment with paroxetine, sertraline, or fluoxetine were observed by metabolizer status. Conclusions Weight gain observed with citalopram may be mediated by CYP2C19 metabolizer status.

We present a methodology for using machine learning for planning treatments. As a case study, we apply the proposed methodology to Breast Cancer. Most of the application of Machine Learning to breast cancer has been on diagnosis and early detection. By contrast, our paper focuses on applying Machine Learning to suggest treatment plans for patients with different disease severity. While the need for surgery and even its type is often obvious to a patient, the need for chemotherapy and radiation therapy is not as obvious to the patient. With this in mind, the following treatment plans were considered in this study: chemotherapy, radiation, chemotherapy with radiation, and none of these options (only surgery). We use real data from more than 10,000 patients over 6 years that includes detailed cancer information, treatment plans, and survival statistics. Using this data set, we construct Machine Learning classifiers to suggest treatment plans. Our emphasis in this effort is not only on suggesting the treatment plan but on explaining and defending a particular treatment choice to the patient.

Background and study aims Concomitant hiatal hernia (HH) repair with transoral incisionless fundoplication (TIF) is a therapeutic option for patients with HH > 2 cm and gastroesophageal reflux disease (GERD). Data comparing this approach with laparoscopic Nissen fundoplication (LNF) are lacking. We performed an exploratory analysis to compare these two approaches' adverse events (AEs) and clinical outcomes. Patients and methods This was a multicenter retrospective cohort study of HH repair followed by LNF versus HH repair followed by TIF in patients with GERD and moderate HH (2–5 cm). AEs were assessed using the Clavien-Dindo classification. Symptoms (heartburn/regurgitation, bloating, and dysphagia) were compared at 6 and 12 months. Results A total of 125 patients with HH repair with TIF and 70 with HH repair with LNF were compared. There was no difference in rates of discontinuing or decreasing proton pump inhibitor use, dysphagia, esophagitis, disrupted wrap, and HH recurrence between the two groups (P > 0.05). The length of hospital stay (1 day vs. 2 days), 30-day readmission rate (0 vs. 4.3 %), early AE rate (0 vs. 18.6 %), and early serious AE rate (0 vs. 4.3 %) favored TIF (all P

A public awareness campaign is a tool of social marketing technique. The quality of awareness campaign is determined based on its effectiveness which is evaluated by its impact on the audience. To know the awareness related to major media campaigns, during the COVID-19 pandemic related to COVID-appropriate behaviour, a survey tool was designed and administered in online mode among 200 young respondents from Varanasi district of Uttar Pradesh, India. Data were collected through Google forms shared via various social platforms and snowball sampling technique with age and area related restrictions. The media campaign which made a great impact on the mind and heart of the respondents were “Do gaj doori mask hai jaroori (Mask and maintaining distance of two yards is necessary) ” and “Jab tak dawai nahi tab tak dhilai nahi (No carelessness till a medicine is recommended)” The sources which made people aware were "caller tune" followed by "family and friends" . Almost all components of COVID-19 appropriate behaviour were known to the respondents except, seeking COVID-19 related information from reliable sources and refraining from sharing unverified social media posts. This research throws light on the interventions that can be more impactful and will thus help in better designing and dissemination of awareness campaigns in future.

Background: Aging leads to loss of skeletal muscle, diminished muscle strength, and decline in physical functions. Objective: This study evaluates Withania somnifera and some dietary interventions to combat muscle weakness in aging rats. Materials and methods: Rats (12–13 months old) corresponding to a human age of 60–65 years were assigned to various groups and given orally a standardized W. somnifera extract (WSE, 500 mg/kg) or a protein cocktail comprising soybean (1.5 g/kg) and quinoa (1 g/kg) or a combination of WSE and the protein cocktail or whey protein (1 g/kg) as a reference standard or only resistance exercise for 60 days. Grip strength and blood glucose levels were monitored weekly. At the end of the treatment, total protein, inflammatory markers (CRP, IL-6 and TNF-α), AMPK, malondialdehyde, glutathione, antioxidant enzymes and apoptotic regulator genes (Bax and Bcl-2) were assayed. The biceps brachii muscle of all animals was subjected to histomorphological study. Results: All treatments successfully attenuated aging-elevated glucose, CRP, IL-6, TNF-α, AMPK, malondialdehyde, and Bax levels. A significant restoration of the aging-depleted total protein levels, glutathione, superoxide dismutase, catalase, and Bcl-2 was noted in the treatment groups. An increase in grip strength and greater biceps mass with all treatments indicated regaining of the frail aging muscle's strength and functionality. The WSE + protein treatment elicited the best results among all treatment groups to optimize muscle strength. Conclusion: All the interventions curbed muscle loss and strengthened the skeletal muscle by reducing inflammation, oxidative stress and apoptosis, and increasing ATP availability to the muscle.

Background: Nishamalaki is an Ayurvedic herbal formulation used to treat type 2 diabetes mellitus (T2DM), comprises Emblica officinalis and Curcuma longa. Objective(s): One of the main cause of T2DM is Insulin Resistance (IR) hence, this study was planned to evaluate IR lowering effect of a standardized Nishamalaki extract “EmbliQur” in high-fat diet (HFD) and streptozotocin (STZ) induced T2DM rats. Materials and methods: Curcuminoids (23.89% w/w), gallic acid (5.27% w/w) and tannins (25.44% w/w) were quantified from EmbliQur. Rats were fed HFD throughout the study of 45 days and received STZ (40 mg/kg, i.p) on the 15th day of the study. Rats with more than 250 mg/dl of fasting blood glucose level (FBGL) were considered diabetic and selected for administration of EmbliQur (500 mg and 1000 mg/kg) or the standard drug metformin (120 mg/kg, p.o) from the 18th day of the study for the next 27 days. FBGL and insulin levels of all rats were measured weekly and an oral glucose tolerance test (OGTT) was done at the end of the study. The values of FBGL and insulin were used to calculate IR by the HOMA-IR, QUICKI and Matsuda methods. Results: Rats treated with STZ/HFD had significantly higher than normal FBGL and insulin levels throughout the study and exhibited skewed IR indices in the above three methods of IR assessment. EmbliQur treatment successfully lowered the HFD/STZ-elevated BGL and insulin levels, and ameliorated IR in all models of IR evaluation. Conclusion: EmbliQur 1000 mg/kg was noted to be more effective than EmbliQur 500 mg/kg in alleviating IR.

ABSTRACT Candida albicans is the leading cause of endogenous fungal endophthalmitis; however, its pathobiology studies are limited. Moreover, the contribution of host factors in the pathogenesis of Candida endophthalmitis remains unclear. In the present study, we developed a murine model of C. albicans endogenous endophthalmitis and investigated the molecular pathobiology of ocular candidiasis and blood-retinal barrier permeability. Our data show that intravenous injection of C. albicans in immunocompetent C57BL/6 mice led to endogenous endophthalmitis without causing mortality, and C. albicans was detected in the eyes at 3 days postinfection and persisted for up to 10 days. The intraocular presence of C. albicans coincided with a decrease in retinal function and increased expression of inflammatory mediators (tumor necrosis factor alpha [TNF-α], interleukin 1β [IL-1β], MIP2, and KC) and antimicrobial peptides (human β-defensins [hBDs] and LL37) in mouse retinal tissue. C. albicans infection disrupted the blood-retinal barrier (BRB) by decreasing the expression of tight junction (ZO-1) and adherens junction (E-cadherin, N/R-cadherin) proteins. In vitro studies using human retinal pigment epithelial (ARPE-19) cells showed time-dependent activation of eIF2α, extracellular signal-related kinase (ERK), and NF-κB signaling and decreased activity of AMP-activated protein kinase (AMPK) leading to the induction of an inflammatory response upon C. albicans infection. Moreover, C. albicans-infected cells exhibited increased cellular permeability coinciding with a reduction in cellular junction proteins. Overall, our study provides new insight into the molecular pathogenesis of C. albicans endogenous endophthalmitis. Furthermore, the experimental models developed in the study can be used to identify newer therapeutic targets or test the efficacy of drugs to treat and prevent fungal endophthalmitis. IMPORTANCE Patients with candidemia often experience endophthalmitis, a blinding infectious eye disease. However, the pathogenesis of Candida endophthalmitis is not well understood. Here, using in vivo and in vitro experimental models, we describe events leading to the invasion of Candida into the eye. We show that Candida from the systemic circulation disrupts the protective blood-retinal barrier and causes endogenous endophthalmitis. Our study highlights an important role of retinal pigment epithelial cells in evoking innate inflammatory and antimicrobial responses toward C. albicans infection. This study allows a better understanding of the pathobiology of fungal endophthalmitis, which can lead to the discovery of novel therapeutic targets to treat ocular fungal infections.

Viruses are known to hijack the intracellular organelles, including mitochondria, endoplasmic reticulum, lipid droplets, and cytoskeleton to promote its replication. The host responds to invading viruses by mounting antiviral responses and rearrangement of its organelles. In particular, the mitochondria are one of the target organelles exploited by viruses and their proteins to suppress the host antiviral response. In this review, we have comprehensively summarized the impact of mitochondrial dynamics in modulating antiviral response during emerging and re-emerging RNA virus infections caused by genus Flavivirus (Dengue virus, Zika virus, Hepatitis C virus), and SARS-CoV-2, the causative agent of COVID-19 pandemic. In addition to knowledge gaps in mitochondria-virus interaction studies, we discuss recent advancements in therapeutics regulating the mitochondrial dynamics to combat viral infections.

Sterilization of ultra-high molecular weight polyethylene (UHMWPE) based composites used for acetabular cup liner via UV or gamma-irradiation before surgery is inevitable. Thus, understanding the alteration of mechanical properties and wear resistance of cup liner via irradiation process requires investigation. This paper aims to understand the effect of UV (0.03 J/cm2) and gamma (25 kGy) irradiation on mechanical properties and scratch resistance of compression molded UHMWPE composites reinforced with alumina (Al2O3), hydroxyapatite (HAp) and carbon nanotubes (CNTs). After irradiation, nearly 100% increased crystallinity of polyethylene, due to recrystallization, helped in enhancing the hardness and elastic modulus by ~1.5 times compared to that of as-processed UHMWPE (Hardness: ~70 MPa and Elastic modulus: ~1.25 GPa). The recrystallization was not favored by the presence of nano-reinforcements in irradiated UHMWPE based nanocomposites, and caused deterioration in the mechanical properties. The micro-scratch results revealed the remarkable wear resistance (i.e., 1.5 to 2 times lower wear rate) of irradiated samples than that of as-processed samples. Mouse fibroblast L929 in vitro cell culture test confirmed the cytocompatibility of irradiated samples. This study indicated that the UV and gamma irradiated UHMWPE nanocomposites are the challenging candidates as acetabular cup liner.

Context: The term “dental anxiety” (DA) refers to the feeling of uneasiness one undergoes during their appointment. Sense of coherence (SoC) is known to be capable of strengthening resilience and developing a subjectively positive state of health. There have been scarce studies showing the association between these two variables. Aim: The present study correlates DA and SoC among patients visiting outpatient department for the first time of a dental college in Chhattisgarh. Materials and Methods: A cross-sectional, questionnaire study was conducted among 400 participants. SoC and DA were measured using Antonovosky's Modified DA Scale and SoC Scale (SoC 13), respectively. The Chi-square test and Pearson's correlation coefficient were used. The analysis was done using the SPSS software version 16.0. Results: Out of 400 participants, the mean age was 37.5, where the number of male participants was high (male = 265 and female = 135). 44.8% of the study participants were slightly anxious. DA according to the age and gender was found to be statistically insignificant (P ≤ 0.896), (P ≤ 0.171), respectively. The overall SoC among the study population was low and a statistically significant association between SoC and age (P ≤ 0.046) was seen. A statistically significant association was found between SoC and gender (P ≤ 0.001). The results stated that SoC is inversely proportional to DA (r = −0.97). Conclusions: The present study reflects that DA and SoC have inverse correlation.

Objective: Tuberculosis (TB) poses a huge socioeconomic burden and remains listed among the top ten causes of deaths across the globe, despite enormous efforts of health agencies and researchers. The primary concern in a relatively slower pace of curbing TB is the emergence of multi-drug resistance and difficulty in tracking antibiotic consumption. Methods: We propose here a biometric-linked digital means of antibiotic prescription data collection and its utility for various epidemiological assessments. Results: In this short communication, we propose here, a visionary workflow to explore the use of biometric identification system to gather the antibiotic prescription information for tuberculosis cases and real-time monitoring over a global scale. Our proposal is mainly aimed at collection of antibiotic prescription data at clinician level and point of sales level using a simple fingerprint-based biometric approach and its linkage to unique biometric IDs such as Aadhar in India and related systems in other countries. Conclusion: The online server and web-interface are aimed at facilitating the health organizations and medical councils to monitor the antibiotic prescription and their consumption in real time. This will not only augment the existing policy-making regarding drug-resistance programs but also promote the collection and downstream exploratory analysis of huge amount of data to get a deeper insight into the epidemiology of tuberculosis and related diseases.

Hypothyroidism is the most frequent consequence of the interaction of a large variety of drugs, environmental pollutants and industrial chemicals with the thyroid gland. It is associated with diminished endocrine function which may lead to hyperlipidemia, diabetes, Alzheimer’s disease, weight gain, and other metabolic disorders. The present study evaluates the pro-thyroid activity of a bioactive fraction from a polyherbal teabag in rats with hypothyroidism induced by propylthiouracil. The teabag was formulated to stimulate synthesis and/or release of T4 and affectthe conversion of T4 to T3. Phytoconstituents of the polyherbal teabag are potent antioxidants that may be responsible for the pro-thyroid activity. The tea-extract (1000 mg) was found to contain 1076 μg of gallic acid and 1131 μg of rutin from HPTLC analysis. Rats received propylthiouracil (8 mg/kg) for the first 15days followed by the polyherbal tea-extract (500, 1000 and 1500 mg/kg), the standard drug levothyroxine (0.1 mg/kg), aerobic exercise, and a combination of tea-extract (1000 mg/kg) and aerobic exercise daily along with propylthiouracil for the next 30 days. Finally, rats received their respective treatments alone without propylthiouracil for 15 more days. Lipid profile and levels of glucose, insulin, T3, T4, TSH, cortisol, homocysteine, creatinine, uric acid, malondialdehyde, glucose-6 phosphatase, and endogenous antioxidants were determined. All treatments attenuated significantly the propylthiouracil-elevated TSH, homocysteine, creatinine, uric acid, glucose-6-phosphatase, insulin, and malondialdehyde levels, and restored favorably the propylthiouracil-altered lipid profile, T3, T4, and endogenous antioxidant levels. The polyherbal tea-extract (1000 and 1500 mg/kg) treatment and thecombination treatment of tea-extract (1000 mg/kg) with aerobic exercise displayed significant restoration of the suboptimalthyroid function. This may be due to a favorablemodulation ofthe hypothalamic-pituitary–thyroid and the hypothalamic–pituitary–adrenal axes.

Effect of various stimuli (concentration, pH, temperature and salt) have been investigated, in aqueous isosorbide (sugar based) spacer based cationic gemini surfactant with hexadecyl chain (16-Isb-16), using spectroscopic and physico-chemical techniques (dynamic light scattering, DLS; nuclear magnetic resonance, NMR; transmission electron microscopy, TEM; polarizing optical microscopy; POM; zeta (ζ)-potential; count rate; pH and conductometry). An interesting phenomenon of micelle to vesicle transition (MVT) has been observed upon dilution. pH sensitive systems, including micelles and vesicles, are found in the solution without changing the pH externally. For external pH change (in the acidic range), DLS data revealed that vesicles are present near the neutral pH. The morphological transitions were confirmed by TEM and POM. ζ data show the conversion of positively charged aggregates to neutral ones. MVT has also been checked by increasing the temperature or adding a salt (NaCl, NaBr, NaNO3 or sodium salicylate; NaSal). Heating induces a transition from micelles to vesicles near ∼40–45 °C while salt addition causes a reverse effect (vesicle to micelle). The transition has been found to be dependent on concentration/nature of salt. The study provides a simple and effective way of tuning the micellar morphology. Keywords: Isosorbide, Cationic gemini surfactant, Micelle-Vesicle-Micelle Transition (MVMT), 1H NMR, TEM, Dynamic light scattering

Point vacancies are the most common defects in a carbon nanotube (CNT) lattice. However, there is no standard technique to identify these defects. Moreover, the effect of such vacancies on the vibrational properties of CNTs is unknown. Therefore, this paper presents the first-ever technique for identification of vacancy defects in single-walled carbon nanotubes (SWCNT) using their vibrational analyses and machine learning. 240 SWCNT samples were modelled using molecular-structural-mechanics-approach and their modes obtained using finite element analyses. Then, an analytical expression for fundamental vibration frequency of a vacancy defective SWCNT was derived using log-linear multiple regression. This frequency is found to decrease with: (i) increase in the magnitude of point vacancies; (ii) decrease in diameter; and (iii) increase in length. A polynomial support vector machine (SVM) was developed that successfully classifies pristine and vacancy defective SWCNT samples at test accuracy greater than 90%. The proposed technique for identification of point vacancies combines the developed SVM classification with inverse estimation using the derived expression. This technique will be useful for the most crucial characterization of SWCNTs, i.e., characterizing pristine and vacancy defective samples. The derived expression will be useful in predicting vibration response of vacancy defective SWCNTs, and deciding their applications.

Introduction: MSX1 protein, a homeobox transcriptional regulator plays a significant role in various developmental processes of the mammalian system such as limb-pattern formation, craniofacial development, in particular, odontogenesis, and tumor growth inhibition. Several studies have been performed on MSX1 at the genomic and transcriptomic levels. However, there is a lack of information on its structural and conformational aspects. Objective: For better understanding of the molecular mechanism of MSX1, the present study aims to conduct a detailed in-silico analysis of this protein in terms of its physicochemical properties, secondary and tertiary structure predictions, interacting partners, and phylogenetic relationship with other orthologs. Methods: The sequence of the MSX1 protein from Homo sapiens was retrieved in the FASTA format from the National Center for Biotechnology Information (NCBI). The standard bioinformatic tools were further used to characterize and model the structure of this protein. Results: The in-silico characterization of MSX1 revealed that it is a basic, non-polar, and thermostable globular protein mainly localized in the nucleus. This protein is extremely rigid due to the presence of high proline content. The phylogenetic and synteny analysis revealed that the gene is highly conserved at the level of the amino acid sequences, but underwent several modifications at the genomic level in the course of evolution possibly to attain the diverse function. Major part of this protein is a random coil, making it suitable for interaction with other proteins. Subcellular localization and protein-protein interaction suggested that the protein may act as a secretory protein and play a crucial role in regulating several developmental processes. Docking analysis suggested that the MSX1 protein may interact with other proteins and form complexes to carry out its function. Conclusion: The structural characterization of this protein will help to better understand its molecular mechanism of action. In addition, the predicted 3-D model would act as a base for further understanding of the protein's other functional potential.

Coagulation factor XIII (FXIII) circulates in plasma as a pro-transglutaminase heterotetrameric complex (FXIIIA2B2), which upon activation by thrombin and calcium covalently crosslinks preformed fibrin polymers. The heterotetrameric complex is composed of a catalytic FXIIIA2 subunit and a protective/regulatory FXIII-B2 subunit coded by F13A1 and F13B genes, respectively. The catalytic FXIIIA2 subunit is encoded by the F13A1 gene, expressed primarily in cells of mesenchymal origin, whereas the FXIIIB subunit encoded by the F13B gene is expressed and secreted from hepatocytes. The plasma FXIIIA2 subunit, which earlier was believed to be secreted from cells of megakaryocytic lineage, is now understood to result primarily from resident macrophages. The regulation of the FXIII subunits at the genetic level is still poorly understood. The current study adopts a purely bioinformatic approach to analyze the temporal, time-specific expression array-data corresponding to both the subunits in specific cell lineages, with respect to the gene promoters. We analyze the differentially expressed genes correlated with F13A1 and F13B expression levels in an array of cell types, utilizing publicly available microarray data. We attempt to understand the regulatory mechanism underlying the variable expression of FXIIIA2 subunit in macrophages (M0, M1, M2 and aortic resident macrophages). Similarly, the FXIIIB2 subunit expression data from adult, fetal hepatocytes and embryonic stem cells derived hepatoblasts (hESC-hepatoblast) was analyzed. The results suggest regulatory dependence between the two FXIII subunits at the transcript level. Our analysis also predicts the involvement of the FXIIIA2 subunit in macrophage polarization, plaque stability, and inflammation.

Bone injuries occur due to various traumatic and disease conditions. Healing of bone injury occurs via a multi-stage intricate process. Body has the potential to rectify most of the bone injuries but some severe traumatic cases with critical size defects may require interventions. Autografts are still considered the “gold standard” for fracture healing but due to limitations associated with it, new alternatives are warranted. The field of orthobiologics has provided novel approaches using scaffolds, bioactive molecules, stem cells for the treatment of bone defects. Phyto-bioactives have been widely used in alternative medicine and folklore practices for curing bone ailments. It is believed that different bioactive constituents in plants work synergistically to give the therapeutic efficacy. Bioactives in plants extracts act upon different signal transduction pathways aiding in bone healing. The present review focuses on the use, chemical composition, mode of delivery, mechanism of action, and possible future strategies of three medicinal plants popularly used in traditional medicine for bone healing: Cissus quadrangularis, Withania somnifera and Tinospora cordifolia. Plants extracts seem to be a natural and non-toxic therapeutic alternative in treating bone injuries. Most of the studies on bone healing for these plants have reported oral administration of the extracts and presented them as a safe alternative without any side effects despite giving higher doses. Forthcoming studies could be directed towards the local delivery of extracts at the defect site. Unification of herbal extracts and orthobiologics could be an interesting direction in the field of bone healing in future. The present review intends to provide a bird’s eye view of different strategies used in bone healing, mechanisms involved and future direction of advancements using phytobioactives and orthobiologics.

During brain development, neurite formation plays a critical role in neuronal communication and cognitive function. In the present study, we compared developmental changes in the expression of crucial markers that govern the functional activity of neurons, including somatostatin (SST), choline acetyltransferase (ChAT), tyrosine hydroxylase (TH), brain nitric oxide synthase (bNOS), gamma-aminobutyric acid (GABA), glutamic acid decarboxylase (GAD-65) and synaptic vesicle protein synaptophysin (SYP) in non-differentiated and retinoic acid (RA)-induced differentiated SH-SY5Y cells. We further determined the role of SST in regulating subcellular distribution and expression of neurotransmitters. Our results indicate that SST potentiates RA-induced differentiation of SH-SY5Y cells and involves regulating the subcellular distribution and expression of neurotransmitter markers and synaptophysin translocation to neurites in a time-dependent manner, anticipating the therapeutic implication of SST in neurodegeneration.

Several RNA viruses, including SARS-CoV-2, can infect or use the eye as an entry portal to cause ocular or systemic diseases. Povidone-Iodine (PVP-I) is routinely used during ocular surgeries and eye banking as a cost-effective disinfectant due to its broad-spectrum antimicrobial activity, including against viruses. However, whether PVP-I can exert antiviral activities in virus-infected cells remains elusive. In this study, using Zika (ZIKV) and Chikungunya (CHIKV) virus infection of human corneal and retinal pigment epithelial cells, we report antiviral mechanisms of PVP-I. Our data showed that PVP-I, even at the lowest concentration (0.01%), drastically reduced viral replication in corneal and retinal cells without causing cellular toxicity. Antiviral effects of PVP-I against ZIKV and CHIKV were mediated by direct viral inactivation, thus attenuating the ability of the virus to infect host cells. Moreover, one-minute PVP-I exposure of infected ocular cells drastically reduced viral replication and the production of infectious progeny virions. Furthermore, viral-induced (CHIKV) expression of inflammatory genes (TNF-α, IL-6, IL-8, and IL1β) were markedly reduced in PVP-I treated corneal epithelial cells. Together, our results demonstrate potent antiviral effects of PVP-I against ZIKV and CHIKV infection of ocular cells. Thus, a low dose of PVP-I can be used during tissue harvesting for corneal transplants to prevent potential transmission of RNA viruses via infected cells.

Obesity is one of the major social and health problems globally and often associated with various other pathological conditions. In addition to unregulated eating behaviour, circulating peptide-mediated hormonal secretion and signaling pathways play a critical role in food intake induced obesity. Amongst the many peptides involved in the regulation of food-seeking behaviour, somatostatin (SST) is the one which plays a determinant role in the complex process of appetite. SST is involved in the regulation of release and secretion of other peptides, neuronal integrity, and hormonal regulation. Based on past and recent studies, SST might serve as a bridge between central and peripheral tissues with a significant impact on obesity-associated with food intake behaviour and energy expenditure. Here, we present a comprehensive review describing the role of SST in the modulation of multiple central and peripheral signaling molecules. In addition, we highlight recent progress and contribution of SST and its receptors in food-seeking behaviour, obesity (orexigenic), and satiety (anorexigenic) associated pathways and mechanism.

ABSTRACT Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by adaptive and innate immune system dysregulation. Recent work has revealed moderate alteration of gut microbial communities in subjects with MS and in experimental, induced models. However, a mechanistic understanding linking the observed changes in the microbiota and the presence of the disease is still missing. Chloroform-resistant, spore-forming bacteria, which primarily belong to the classes Bacilli and Clostridia in the phylum Firmicutes, have been shown to exhibit immunomodulatory properties in vitro and in vivo, but they have not yet been characterized in the context of human disease. This study addresses the community composition and immune function of this bacterial fraction in MS. We identify MS-associated spore-forming taxa (primarily in the class Clostridia) and show that their presence correlates with impaired differentiation of IL-10-secreting, regulatory T lymphocytes in vitro. Colonization of antibiotic-treated mice with spore-forming bacteria allowed us to identify some bacterial taxa favoring IL-10+ lymphocyte differentiation and others inducing differentiation of proinflammatory, IFN-γ+ T lymphocytes. However, when fed into antibiotic-treated mice, both MS and control-derived spore-forming bacteria were able to induce similar IL-10-expressing Treg immunoregulatory responses, thus ameliorating symptoms of experimental allergic encephalomyelitis (EAE). Our analysis also identified Akkermansia muciniphila as a key organism that may interact either directly or indirectly with spore-forming bacteria to exacerbate the inflammatory effects of MS-associated gut microbiota. Thus, changes in the spore-forming fraction may influence T lymphocyte-mediated inflammation in MS. This experimental approach of isolating a subset of microbiota based on its functional characteristics may be useful to investigate other microbial fractions at greater depth. IMPORTANCE To address the impact of microbiome on disease development, it is essential to go beyond a descriptive study and evaluate the physiological importance of microbiome changes. Our study integrates computational analysis with in vitro and in vivo exploration of inflammatory properties of spore-forming microbial communities, revealing novel functional correlations. We specifically show that while small differences exist between the microbiomes of MS patients and healthy subjects, these differences are exacerbated in the chloroform-resistant fraction. We further demonstrate that, when purified from MS patients, this fraction is correlated with impaired immunomodulatory responses in vitro. Author Video: An author video summary of this article is available.

Factor XIII (FXIII) is a predominant determinant of clot stability, strength, and composition. Plasma FXIII circulates as a pro-transglutaminase with two catalytic A subunits and two carrier-protective B subunits in a heterotetramer (FXIII-A2B2). FXIII-A2 and -B2 subunits are synthesized separately and then assembled in plasma. Following proteolytic activation by thrombin and calcium-mediated dissociation of the B subunits, activated FXIII (FXIIIa) covalently cross links fibrin, promoting clot stability. The zymogen and active states of the FXIII-A subunits have been structurally characterized; however, the structure of FXIII-B subunits and the FXIII-A2B2 complex have remained elusive. Using integrative hybrid approaches including atomic force microscopy, cross-linking mass spectrometry, and computational approaches, we have constructed the first all-atom model of the FXIII-A2B2 complex. We also used molecular dynamics simulations in combination with isothermal titration calorimetry to characterize FXIII-A2B2 assembly, activation, and dissociation. Our data reveal unequal pairing of individual subunit monomers in an otherwise symmetric complex, and suggest this unusual structure is critical for both assembly and activation of this complex. Our findings enhance understanding of mechanisms associating FXIII-A2B2 mutations with disease and have important implications for the rational design of molecules to alter FXIII assembly or activity to reduce bleeding and thrombotic complications.

Coagulation factor XIII (FXIII) is a plasma-circulating heterotetrameric pro-transglutaminase complex that is composed of two catalytic FXIII-A and two protective/regulatory FXIII-B subunits. FXIII acts by forming covalent cross-links within a preformed fibrin clots to prevent its premature fibrinolysis. The FXIII-A subunit is known to have pleiotropic roles outside coagulation, but the FXIII-B subunit is a relatively unexplored entity, both structurally as well as functionally. Its discovered roles so far are limited to that of the carrier/regulatory protein of its partner FXIII-A subunit. In the present study, we have explored the co-presence of protein excipients in commercial FXIII plasma concentrate FibrogamminP by combination of protein purification and mass spectrometry-based verification. Complement factor H was one of the co-excipients observed in this analysis. This was followed by performing pull down assays from plasma in order to detect the putative novel interacting partners for the FXIII-B subunit. Complement system proteins, like complement C3 and complement C1q, were amongst the proteins that were pulled down. The only protein that was observed in both experimental set ups was alpha-2-macroglobulin, which might therefore be a putative interacting partner of the FXIII/FXIII-B subunit. Future functional investigations will be needed to understand the physiological significance of this association.

The authors wish to correct the following erratum in this paper [...]

Congenital FXIII deficiency is a rare bleeding disorder in which mutations are detected in F13A1 and F13B genes that express the two subunits of coagulation FXIII, the catalytic FXIII-A, and protective FXIII-B. Mutations in FXIII-B subunit are considerably rarer compared to FXIII-A. Three mutations in the F13B gene have been reported on its structural disulfide bonds. In the present study, we investigate the structural and functional importance of all 20 structural disulfide bonds in FXIII-B subunit. All disulfide bonds were ablated by individually mutating one of its contributory cysteine’s, and these variants were transiently expressed in HEK293t cell lines. The expression products were studied for stability, secretion, the effect on oligomeric state, and on FXIII-A activation. The structural flexibility of these disulfide bonds was studied using classical MD simulation performed on a FXIII-B subunit monomer model. All 20 FXIII-B were found to be important for the secretion and stability of the protein since ablation of any of these led to a secretion deficit. However, the degree of effect that the disruption of disulfide bond had on the protein differed between individual disulfide bonds reflecting a functional hierarchy/diversity within these disulfide bonds.

Despite flaviviruses remaining the leading cause of systemic human infections worldwide, ocular manifestations of these mosquito-transmitted viruses are considered relatively uncommon in part due to under-reporting. However, recent outbreaks of Zika virus (ZIKV) implicated in causing multiple ocular abnormalities, such as conjunctivitis, retinal hemorrhages, chorioretinal atrophy, posterior uveitis, optic neuritis, and maculopathies, has rejuvenated a significant interest in understanding the pathogenesis of flaviviruses, including ZIKV, in the eye. In this review, first, we summarize the current knowledge of the major flaviviruses (Dengue, West Nile, Yellow Fever, and Japanese Encephalitis) reported to cause ocular manifestations in humans with emphasis on recent ZIKV outbreaks. Second, being an immune privilege organ, the eye is protected from systemic infections by the presence of blood-retinal barriers (BRB). Hence, we discuss how flaviviruses modulate retinal innate response and breach the protective BRB to cause ocular or retinal pathology. Finally, we describe recently identified infection signatures of ZIKV and discuss whether these system biology-predicted genes or signaling pathways (e.g., cellular metabolism) could contribute to the pathogenesis of ocular manifestations and assist in the development of ocular antiviral therapies against ZIKV and other flaviviruses.

Context: Cataract surgery is one of the most frequently performed intra-ocular surgeries, of these manual Small Incision Cataract Surgery (SICS) is a time tested technique of cataract removal. Any corneal incisional surgery, including cataract surgery, can induce dry eye postoperatively. Various factors have been implicated, of which oneis the inflammation induced by the surgery. Lactoferrin, a glycoprotein present in tears is said to have antiinflammatory effects, and promotes cell growth. It has been used orally in patients of immune mediated dry eye to alleviate symptoms. Aim: This study was aimed to evaluate the dry eyes induced by manual Small Incision Cataract Surgery, and the effect if any, of oral lactoferrin on the dry eyes. Settings and Trial Design: A single centre, prospective randomised controlled trial with a concurrent parallel design. The study was carried out on patients presenting in the OPD of Rohilkhand Medical College hospital for cataract surgery. Materials and Methods: Sixty four patients of cataract surgery were included in the study. Patients with pre-existing dry eyes, ocular disease or systemic disease predisposing to dry eyes were excluded from the study. The selected patients were assigned into two groups by simple randomisation-Control Group A-32 patients that did not receive oral lactoferrin postoperatively. Group B-32 patients that received oral lactoferrin 350 gm postoperatively from day 1 after SICS. All patients were operated for cataract and their pre and postoperative (on days 7, 14, 30 and 60) dry eye status was assessed using the mean tear film break-up time (tBUT) and Schirmer test 1 (ST 1) as the evaluating parameters. Subjective evaluation of dry eye was done using Ocular Surface Disease Index (OSDI) scoring. Data was analysed for 58 patients, as 6 did not complete the follow up. Statistical Analysis: Unpaired t-test was used to calculate the p-values. Result: There was a statistically significant difference between the tBUT values of the Control and Lactoferrin group from day 14 onwards. The tBUT of control group on day 60 was 7.86 (±0.86) seconds as compared to 13.9(± 0.99) seconds in the lactoferrin group. The Schirmer test 1 values also showed a statistically significant difference between the two groups- 15.86 (± 5.83) seconds in the control group versus 30.9 (±1.66) in the lactoferrin group on day 60. OSDI score showed 42.8% patients complaining of at least mild dry eye symptoms in the control group, as compared to 26.6% patients in the lactoferrin group on day 60. Conclusion: Small Incision Cataract Surgery induces dry eye postoperatively. Oral lactoferrin given postoperatively improves tear film status and dry eye after cataract surgery.

Background: Cutaneous melanocytic proliferations are diverse both morphologically as well as in their behavioural patterns. Both dermatologists and pathologists regularly encounter diagnostic dilemmas while interpreting such lesions. Aim: To study all cutaneous premalignant and malignant lesions with respect to their clinical features and histopathological findings. Materials and Methods: A retrospective study was done in the Department of Pathology over a period of 10 years (2004-14) on all the clinically pigmented lesions that were biopsied or excised. Out of these only premalignant and malignant melanocytic lesions were analysed with respect to their important clinical and histologic features. Immunohistochemistry was carried out using HMB-45 and S-100 where indicated. Results: A total of 338 skin cancers were reported, out of these 27, 7.9% were cutaneous malignant melanoma. Premalignant lesions were 33. The mean age for premalignant lesions and melanomas was 43 years and 50.7 years respectively with a male predominance in both groups. The sole of foot/ankle was the most common site of involvement by melanoma (n=8,29.6%) while sun exposed sites like face and scalp were common sites for development of premalignant lesions like dysplastic nevi, lentigo simplex, pigmented seborrheic keratosis and Bowens disease. One case presented as post-traumatic scar tissue which turned out to be desmoplastic melanoma. One case of amelanotic melanoma presented as recurrent painful penile ulcers. Both cases were confirmed on Immunohistochemistry. Conclusion: All pigmented lesions should be regarded as tumours of uncertain malignant potential and treated with complete excision if possible with long term follow up.